(Applicant's Description) Allogeneic bone marrow transplantation has emerged as the preferred therapy for a variety of disorders. Unfortunately, outcome is limited by development of graft-versus-host disease (GvHD) and by opportunistic infection. Of the factors that contribute to the increased frequency and severity of GvHDoccurring after unrelated donor BMT, genotypic matching for HLA-DRB1 and HLA-DQB1 appear to be particularly important. While the present modalities used to prevent GvHD are of benefit, they are not selective in their effects on the immune system, in that responses to opportunistic pathogens are blunted along with the GVH response. Given the importance of HLA class II allodisparities in initiating GVH responses, one of the logical targets for the development of new immune suppressive agents is the CD4 molecule, which plays a critical role in the activation of CD4+ T cells in response to HLA-class II allodisparities. Portions of the CD4 molecule which were predicted to interact with other cell surface molecules were targeted for the design of synthetic peptide analogs with the rationale that through competition, they would interfere with T-cell activation. These molecules have demonstrated immunosuppressive activity in GvHD models which is additive to that of Cyclosporine. The peptides require only short term administration and are selectively active, in that only those T-cells which encounter antigen in the presence of peptide are affected, while other T cells remainfunctionally intact. No toxicity has been observed to date. One cyclic heptapeptide, 802-2, is now ready for clinical investigation. Three scientific projects are proposed. Based on further structural and functional studies, derivatives of our current lead compounds will be developed. The 802-2 peptide will be further characterized in in vitro and animal models, as will new compounds that are developed. In conjunction with the National Marrow Donor Program, a multicenter trial will be conducted to test the clinical efficacy of 802-2 peptide in unrelated donor BMT. The effects of 802-2 peptide on human lymphocytes after in vivo or in vitro exposure will also be determined. The ultimate goals of these investigations are: (1) to improve clinical outcome for our present patient populations, and (2) to reduce or eliminate the risk of GvHD arising from donor-host HLA class II disparities which presently excludes at least a third of otherwise appropriate candidates from allogeneic transplantation. The composite information gained should allow assessment of the efficacy of the present generation of CD4 analogs as well as the design and preclinical testing of next generation products.
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